1. Field of the Invention
The invention relates to bacterial antibiotic resistance. More particularly, the invention relates to compositions and methods for overcoming bacterial antibiotic resistance.
2. Background of the Invention
Bacterial antibiotic resistance has become one of the most important threats to modern health care. Cohen, Science 257:1051–1055 (1992) discloses that infections caused by resistant bacteria frequently result in longer hospital stays, higher mortality and increased cost of treatment. Neu, Science 257:1064–1073 (1992) discloses that the need for new antibiotics will continue to escalate because bacteria have a remarkable ability to develop resistance to new agents rendering them quickly ineffective.
The present crisis has prompted various efforts to elucidate the mechanisms responsible for bacterial resistance. Coulton et al. Progress in Medicinal Chemistry 31:297–349 (1994) teach that the widespread use of penicillins and cephalosporins has resulted in the emergence of β-lactamases, a family of bacterial enzymes that catalyze the hydrolysis of the β-lactam ring common to presently used antibiotics. More recently, Dudley, Pharmacotherapy 15: 9S–14S (1995) has disclosed that resistance mediated by β-lactamases is a critical aspect at the core of the development of bacterial antibiotic resistance.
Attempts to address this problem through the development of β-lactamase inhibitors have had limited success. Sutherland, Trends Pharmacol Sci 12: 227–232 (1991) discusses the development of the first clinically useful β-lactamase inhibitor, clavulanic acid, which is a metabolite of Streptomyces clavuligerus. Coulton et al. (supra) disclose two other such semi-synthetic inhibitors, sulbactam and tazobactam presently available. Coulton et al. (supra) also teach that in combination with β-lactamase-susceptible antibiotics, β-lactamase inhibitors prevent antibiotic inactivation by β-lactamase enzymes, thereby producing a synergistic effect against β-lactamase producing bacteria.
Rahil and Pratt, Biochem. J. 275: 793–795 (1991), and Li et al., Bioorg. Med. Chem. 5: 1783–1788 (1997) teach that β-lactamase enzymes are inhibited by phosphonate monoesters. Song and Kluger, Bioorg. Med. Chem. Lett., 4, 1225–1228 (1994), teaches that E. Coli RTEM β-lactamase is inhibited by benzylpenicillin methyl phosphate.
Laird and Spence, J. C. S. Perkin Trans. II 1434 (1973), Kazlauskas and Whitesides, J. Org. Chem. 50: 1069–1076 (1985), Chantrenne, Compte. Rend. Trav. Lab. Carlsberg Ser. Chim. 26: 297 (1948), and Maracek and Griffith, J. Am. Chem. Soc. 92: 917–921 (1970), report synthesis and solvolysis studies of acyl phosphate and acyl phosphonate compounds. Kluger et al., Can. J. Chem. 74: 2395–2400 discloses that aminoacyl phosphates are useful as biomimetically activated amino acids.
The availability of only a few compounds however, is insufficient to counter the constantly increasing diversity of β-lactamases for which a variety of novel and distinct inhibitors has become a necessity. There is, therefore, a need for the ability to identify new β-lactamase inhibitors. The development of fully synthetic inhibitors would greatly facilitate meeting this need. Ideally, certain embodiments of such inhibitors would also bind bacterial DD-peptidases, thus potentially acting both as β-lactamase inhibitors and as antibiotic agents.